Pharmaceutical compositions with dimethyl sulfoxide

ABSTRACT

COMPOSITIONS AND DOSAGE FORMS FOR TOPICAL ADMINISTRATION OF DIMETHHYL SULFOXIDE AS A PHARMACEUTICAL ARE DESCRIBED, WHEREIN THE DIMETHYL SULFOXIDE CONCENTRAAATION IS BETWEEN ABOUT 10% AND ABOUT 90% AND WHEREIN DILUENTS, TOGETHER WITH DIMETHYL SULFOXIDE-SOLUBLE LIPOIDAAL THICKENING AGENTS, WATER-DISPERSIBLE THICKENING AGENTS AND EMULSION-BASE THICKENING AGENTS, ARE INCLUDED IN SUCH COMPOSITIONS. SUPPOSITORIES CONTAINING DIMETHYL SULFOXIDE (DMSO) ARE ALSO DESCRIBED. LIQUID FORMULATIONS FOR TOPICAL APPLICATION INCLUDING AT LEAST 10% DMSO AND AND AAQUEOUS DILUENT IN SPRAY CONTAINERS ARE ALSO PROVIDED.

United States Patent 3,740,420 PHARMACEUTECAL COMPOSITIONS WITH DIMETHYL SULFOXIDE Robert J. Herschler, Camas, Wash, and Stanley W. .l'acob,

Oswego, Greg; said Jacob assignor to Crown Zellcrbach Corporation, San Francisco, Calif.

No Drawing. Continuation-impart of application Ser. No. 686,295, Nov. 28, 1967, new Patent No. 3,549,770, dated Dec. 22, 1970, which is a continuation-in-part of applications Ser. Nos. 329,205, 329,208, 329,209, 329,238, and 329,271, ail Dec. 9, 1963, 346,366, Feb. 10, 1964, 417,781, 417,788 and 417,797, all Dec. 11, 1964, all now abandoned. This application Oct. 30, 1970, Ser. No. 85,696

lint. Cl. A6lk 9/00 US. Cl. 424-45 24 Claims ABSTRACT OF THE DISCLOSURE Compositions and dosage forms for topical administration of dimethyl sulfoxide as a pharmaceutical are described, wherein the dimethyl sulfoxide concentration is between about 10% and about 90% and wherein diluents, together with dimethyl sulfoxide-soluble lipoidal thickening agents, water-dispersible thickening agents and emulsion-base thickening agents, are included in such compositions. Suppositories containing dimethyl sulfoxide (DMSO) are also described. Liquid formulations for topical application including at least 10% DMSO and an aqueous diluent in spray containers are also provided.

REFERENCES TO RELATED APPLICATIONS This is a continuation-in-part of our copending US. application Ser. No. 686,295, filed Nov. 28, 1967, now US. Pat. No. 3,549,770, granted Dec. 22, 1970, which is, in turn, a continuation-in-part of applications Ser. Nos. 329,238, entitled Analgesia; 329,208, entitled Relief of Tissue Inflammation and Stimulation of Repair; 329,- 205, entitled Relief of Signs and Symptoms of Arthritis; 329,271, entitled Relief of Signs and Symptoms of Respiratory Distress; and 329,209, entitled Tranquilization, all filed Dec. 9, 1963; Ser. No. 346,366, entitled Control of Microorganisms, filed Feb. 10, 1964; and Ser. Nos. 417,781, entitled Muscle Relaxation; 417,788, entitled Treatment of Burns and Promotion of Skin Grafts, and 417,797, entitled Relieving Symptoms of Vascular Insutficiency, all filed Dec. 11, 1964, all presently now abandoned, except for Ser. No. 686,295.

BACKGROUND OF THE INVENTION This invention relates to compositions and dosage forms of dimethyl sulfoxide for use as a pharmaceutical to treat a variety of signs and symptoms, as will be dis cussed in detail herein. For the various conditions treatable with the compositions of the present invention, a considerable variety of medication and treatment exists. However, each has its limitations due to allergic response or potentially damaging side eifects, restricted spectrum of activity (effective only in limited types of disorders), restricted routes of administration, lack of individual response in a certain percentage of individuals, expense, etc. Therefore, additional agents are constantly being sought which can replace, supplement, or augment existing medication.

In achieving pharmaceutical effects, it is desirable to utilize an agent which is both well tolerated and conveniently administered. In addition to the obvious advantages of patient acceptability, topical application is a particularly advantageous route where treatment of a localized condition is desired since the effect of the agent may be concentrated at the area under treatment for 3,740,420 Patented June 19, 1973 rapid and specific results. Relatively few pharmaceuticals may be effectively applied topically to the skin and mucous membranes of the body cavities, particularly to obtain a response in disorders involving deeper tissues, structures and organs. Thus, with most pharmaceuticals the only alternative to esthetically undesirable localized injections has been generalized systemic medication (necessarily slower acting) through oral administration. Accordingly, it is desirable in the field of medicine to provide new pharmaceutical compositions which are favorably tolerated and are substantially non-toxic at effective levels of administration. It is further desirable to provide pharmaceutical compositions which are effective in a wide range of conditions and which may be administered conveniently by topical administration.

The present invention has as a primary object to provide such new, well-tolerated, substantially non-toxic pharmaceutical compositions and dosage forms which are effective for a wide range of conditions and which may be administered conveniently by the topical route.

Dimethyl sulfoxide (DMSO), originally synthesized in 1866, in a colorless liquid at room temperature which melts at about 18.5 C. and boils at about C. Over the last 25 years it has been used increasingly as an industrial solvent, reaction medium and chemical reactant and a considerable amount of literature has developed on its properties and industrial uses. It has been investigated for toxicity in experimental animals and for several biological functions, namely, as a protectant in freeze preservation of living tissue and as a radio protectant in experimental animals at high doses injected prior to radiation of the animals. Uses have also been discovered by one of the present inventors for dimethyl sulfoxide in the agricultural field, namely, in enhancing penetration of other agents into plants, in controlling plant virus and in stimulating plant metabolic functions. Copending applications have also been filed by one of the applicants hereof concerning other discovered pharmaceutical properties of dimethyl sulfoxide and relating to enhancing animal tissue penetration of physiologically active agents with dimethyl sulfoxide and compositions for this purpose. These include application Ser. No. 753,- 231, filed Aug. 16, 1968, and two contemporaneously filed applications entitled Enhancing Tissue Penetration of Physiologically Active Steroids with DMSO and Pharmaceutical Compositions of DMSO with Physiologically Active Agents, respectively.

SUMMARY OF THE INVENTION Quite surprisingly, in the light of the long history, extensive experimentation, study and evaluation of this compound, it has now been discovered that dimethyl sulfoxide has previously unrecognized valuable and extensive pharmaceutical activity. It has been found to be broadly useful in the treatment of damaged tissue, particularly as an anti-inflammatory agent, and as a stimulant to repair of the damaged tissue, as an analgesic agent, as a muscle relaxant, as an agent for treating vascular insufiiciency and as an agent for treating mental anxiety states and depression. It additionally has particular usefulness in relieving the collective signs and symptoms of certain specific syndromes, namely, respiratory distress, arthritis and burns. Dimethyl sulfoxide is rapidly rendered systemic in the body from all normal routes of administration and, importantly, it may be applied topically to the intact skin or mucous membrane to achieve highly unusual rapid absorption to the affected sites in the body. Based upon this discovery, composition and dosage forms for topical administration have been developed which are especially adapted to utilize the pharmaceutical activity of dimethyl sulfoxide in an efficient manner, particularly in connection with its unique tissue penetration properties, while at the same time avoiding undue side effects.

The composition and dosage forms of the present invention in broad outline constitute topical formulations which comprise from about to about 90% by weight DMSO, an amount of a pharmaceutically acceptable diluent to minimize undesirable side affects consistent with effective penetration of DMSO and either a waterdispersible thickening agent, a DMSO-soluble lipoidal thickening agent, or an emulsion-base thickening agent to impart appropriate properties to the composition for effective and eflicient penetration by topical application to the skin or mucous membranes of a subject. Suppositories containing DMSO are also comprehended by the invention. Also provided are liquid formulations for topical application comprising at least 10% by weight DMSO, an aqueous diluent and, optionally, thickening agents, etc., in spray containers. Such dosage forms are useful for topical application to prevent accidental spilling and undesired contact with the composition. They are particularly suitable for application to mucous membranes of various body orifices. They are also advantageous in providing a more uniform application to both dermal and mucous membrane surfaces. Other aspects of the compositions and dosage forms of this invention will become apparent from the detailed description which follows.

COMPOSITION AND DOSAGE FORMS Dimethyl sulfoxide may be diluted with pharmaceutically acceptable diluents. Particularly useful are hydrophilic, DMSO-soluble or miscible diluents, which term, for the sake of convenience, is intended to include water, itself. Hydrophilic diluents generally lower the freezing point of the DMSO component (which, undiluted freezes at around 65 F.) so that the DMSO compositions remain unfrozen at temperatures normally encountered. As will be described below, especially advantageous results may be obtained by diluting dimethyl sulfoxide with such pharmaceutically acceptable soluble or miscible hydrophilic diluents, especially liquids such as water or glycerin, and including ethanol and saline solution, to form liquid, semisolid and solid formulations containing specified ranges of dimethyl sulfoxide concentration.

As will also be discussed in detail, pharmaceutical excipients may be employed to form advantageous dosage forms of dimethyl sulfoxide and, additionally, adjuvants may be incorporated in such formulations whereit is desired to combine the effects of dimethyl sulfoxide with another pharmaceutical.

However, whatever the formulation, it is required that the dimethyl sulfoxide be applied in a pharmaceutically acceptable form, by which is meant that it be sufficiently purified so that it does not cause any untoward reaction or injury to the body of the subject from contaminants and the like.

Such compositions containing at least about 50% dimethyl sulfoxide along with a minor amount of a pharmaceutically acceptable diluent, such as water, alcohol or glycerol, has been found to be uniquely suitable for skin application. A concentration of at least about 50% dimethyl sulfoxide has been found necessary to efficient, practical penetration of the skin barrier. Lower concentrations for this unique route may thus result in less than the desired effect. On the other hand, with very high concentration of dimehyl sulfoxide, as those substantially above 90%, the undesired side effects of local skin irritation and dehydration, erythema and urticaria increase markedly while no substantial increased benefit is obtained and the rate of DMSO penetration may actually be lessened. Thus, we have found that for dermal application, by diluting the dimethyl sulfoxide with an appropriate hydrophilic diluent, particularly to a concentration of 90% or less, these side effects can be minimized and patient acceptability thereby enhanced consistent with effective results. Therefore, for the highly advantageous administration of dimethyl sulfoxide to the intact skin for its effect on deeper tissue, due to its unusual penetration properties, compositions containing from about 50% to about dimethyl sulfoxide and a pharmaceutical diluent, as exemplified by the 50%, 75% and 90% aqueous dimethyl sulfoxide compositions of following Example 2, have been found uniquely suitable and desirable. Dimethyl sulfoxide-glycerin solutions of 10% to 40% glycerin content are quite advantageous to minimize skin irritation due both to the dilution of the dimethyl sulfoxide and the emollient effect of the glycerin, which tends to soothe the irritation and skin dryness which may be caused by the dimethyl sulfoxide.

For topical application to the mucous membranes of the body, as for example the mouth and throat, nasal passages, eyes, bladder, anal, urethral, and vaginal regions, compositions including dimethyl sulfoxide at a concentration of at least about 10%, preferably 20% to 40%, and including a pharmaceutical diluent, as for example water, alcohol or glycerol, are especially suitable. Dilution of the dimethyl sulfoxide to a concentration of 90% and below is also advantageous in minimizing irritation to the mucous membranes. Thus, 10% to 90% concentrations of dimethyl sulfoxide are suitable for application to mucous membranes and particularly 10% to 90% water solutions.

For the various topical routes, dimethyl sulfoxide may be formulated into highly convenient dosage forms with thickening agents, as illustrated in the examples which follow. Such forms include thickened solutions (paints) or lotions, ointments (including creams and gels), suppositories and the like.

Thickened solutions or lotions, ointments and suppositories may be formed by incorporating with the dimethyl sulfoxide various gelling agents or other thickeners (viscosity increasers) which permit release of the dimethyl sulfoxide to the skin or mucous membranes upon application. These forms are advantageously employed to lessen the run-off from the skin that may occur with the more fluid composition forms, thereby permitting greater mobility for the patient immediately following treatment. Importantly, they also permit more sustained contact of the dimethyl sulfoxide with the treated surfaces and more accurate and controlled dosing. Accidental spilling and undesired contact with the material can also be minimized with these formulations.

It is advantageous to use water-dispersible thickening agents .(i.e., agents dispersible in water to form a homogenous distribution or solution), such as the polyethylene glycols, as they are readily compatible with water or other diluents to be formulated in the compositions and they may be readily washed from the skin following absorption into the skin of the DMSO. Alternatively, an emulsion base may be employed to impart the desired thickening effect, together with the emollient effect of the lipoid phase of the emulsion base, a better spreading and wetting effect and a retardation of the skin-drying effect of the DMSO. When compounded with an emulsion base, the DMSO is incorporated in the water phase thereof. Yet a third category of thickening base which can also impart an emollient effect is provided by DMSO-soluble lipoidal thickening agents.

The water-soluble thickening bases may utilize polyethylene glycols of different viscosities, depending upon the desired consistency and concentration of dimethyl sulfoxide to be incorporated, water-dispersible gums, carboxy vinyl polymers, methyl cellulose, sodium carboxy methyl cellulose, alginates and the like. Dimethyl sulfoxide may be added to the lotion, ointment or suppository base in varying amounts as desired, generally up to 50% or higher, depending on the consistency desired.

The lotions, ointments and suppositories incorporating emulsion bases may contain the usual ingredients to provide the base, as for example a fatty alcohol such as cetyl alcohol, an emulsifier such as lauryl sulfate and water.

Another base may be formulated by combining equal weight amounts of stearic acid, cetyl alcohol, triethanolamine and glycerol monostearate together with water.

The DMSO-soluble lipoidal thickening agents, for example lanolin, cocoa butter or glycerol monostearate, may be combined with DMSO and a diluent in proportions to obtain the desired consistency.

A suppository form is highly advantageous, particularly for the treatment of hemorrhoids. The usual low melting gelling agents or other thickening agents may be employed for this purpose. The dimethyl sulfoxide concentration is usually 20% or below in this form but it may be higher, depending upon the strength of the gelling agent or other thickener. Agents such as polyethylene glycols of varying viscosities, glycerol monostearate and the like may be employed. A high viscosity polyethylene glycol, such as polyethylene glycol 4000, water and 20% dimethyl sulfoxide may be a suitable formulation. By using lower viscosity gelling or other thickening agents of the same type a satisfactory ointment may be made which may be smeared on the involved area to achieve similar results.

The pourable pharmaceutical dosages may be provided and dispensed in graduated containers or containers containing a given volume such as, for example, 1 cc., 2 cc., 5 cc., cc., 20 cc., 100 cc., 200 cc., or 500 cc. The containers With volumes of 20 cc. and above provide convenient multiple dosage forms and those containing a typical single dose, say from 0.5 gram to 20 grams of dimethyl sulfoxide, provide convenient unit dose forms. The practitioner need only open and dispense all or a determined part to a subject. In this way, the dosage may be ascertained and controlled readily by the practitioner. Squeeze tubes (for lotions and ointments) and cotton stick applicators may all be utilized for topical application of the thickened compositions.

The spraying and misting dosage forms of the invention constitute nasal spray bottles, aspirators, misting devices, aerosol bombs and other dispensing containers having liquid spray or mist dispensing means, which containers are charged with fluid formulations comprising at least 10% by weight DMSO and an aqueous diluent, and, optionally, thickening agents, physiological salts and the like. The water component is at least 10% by weight of the composition and preferably at least 50%. The compositions for this purpose are sufiiciently fluid to permit dispensing by spray or mist from the container. They also meet the previously described criteria for penetrability and avoidance of undue side effects.

The following examples are illustrative of the composition and dosage forms of this invention and techniques for their preparation:

Example 1.Compositions of determined amounts Dimethyl sulfoxide is distilled at reduced pressure of under 25 mm. Hg in order to keep the temperature at 90 C. or less, and thereby prevent deterioration. A rapid distillation at 16 mm. Hg and 79 C. head temperature is satisfactory. An inert gas such as nitrogen is preferably used in the distillation process to displace other gases which may adversely affect the purity of the compound. The distilled liquid is filtered through activated charcoal and again distilled. The collected dimethyl sulfoxide is in a pharmaceutically acceptable form, and is transferred to cleaned bottle containers of 100, 200, and 500 ml. volumes. The bottles are stoppered with cleaned closures and identified. Other pharmaceutically purified 100% dimethyl sulfoxide volumes are transferred to 200 cc. bottles graduated to one cc. units, stoppered with cleaned closures and identified. Another volume of 100% dimethyl sulfoxide is transferred to a cleaned 100 cc. bottle and stoppered with a closure filled with a suction bulb and a 10 cc. tube graduated to one cc. units.

Example 2.Pharmaceutica1 solutions of dimethyl sulfoxide One hundred percent dimethyl sulfoxide in a pharmaceutically purified form is collected as shown in Example 1. Dilutions are made with distilled water and transferred to 500 cc. cleaned bottles which are then stoppered with cleaned closures. The dilutions provide separately bottled solutions containing dimethyl sulfoxide at concentrations of 10%, 20%, 50%, 75%, and The bottles are identified and are available for topical or oral application.

Solutions of similar concentrations are also prepared using 0.9% saline (sodium chloride) as the diluent, in order to render the solution isotonic.

The distilled water and saline solutions containing dimethyl sulfoxide at concentrations of 10% and 20% are Berkfield filtered to obtain a sterile form which is placed in cc. bottle containers. The bottles are stoppered. The sterilized solutions are checked for pyrogens with standard rabbit tests.

All of these solutions may be used for further formulation with thickening agents for ultimate use.

Example 3.--Ointment and suppository compositions Suppository and ointment compositions, suitable for rectal, urethral or vaginal use, may be prepared with the following formulations:

Suppository (dimethyl sulfoxide concentration10%):

Percent Dimethyl sulfoxide 10 Water l0 Carbowax polyethylene glycol 1540 30 Carbowax polyethylene glycol 4000 50 Suppository (dimethyl sulfoxide concentration-40%):

Percent Carbowax polyethylene glycol 4000 84 Dimethyl sulfoxide 10 Glycerin 6 Suppository (dimethyl sulfoxide concentration-10%):

Acetylsalicylic acid grains/suppository 10 Carbowax polyethylene glycol 6000 parts 30 Carbowax polyethylene glycol 1540 do 30 Carbowax polyethylene glycol 600 do 30 Dimethyl sulfoxide do 10 Suppository (dimethyl sulfoxide concentrati0I1-2I%):

Cocoa butter gm 450 Water cc v 50 Dimethyl sulfoxide cc Ointment (dimethyl sulfoxide concentration50% Stearic acid gms 40 Cetyl alcohol gms 5 Triethanolamine gms 4.2 Glycerol monostearate gms 4.2 Water cc 40 Dimethyl sulfoxide cc -100 Carbowax is a proprietary name of Union Carbide and the number following is an arbitrary designation related to the viscosity and melting point of the polyethylene glycol, the higher the number the higher the melt point and viscosity. For ointments, the compositions are desirably adjusted for a lower viscosity. DMSO-soluble, lipoidal thickening agents such as glycerol monostearate and cocoa butter may be used. They should be selected to melt at body temperature and release the dimethyl sulfoxide. The concentration of dimethyl sulfoxide preferably may be up to 20%. Higher concentrations of 50% and above may also be employed if the thickening agent can thicken a higher quantity.

The thickening agents may be melted in a water bath, the dimethyl sulfoxide and any other active ingredients added with mixing. The mix may be cooled to 50 C. and

. poured into suppository molds to form the product.

Example 4.Suppository composition The following ingredients are combined and the mixture is formed into a suppository which contains dimethyl sulfoxide at a concentration of about Carbowax gn1s 500 Water cc 50 Dimethyl sulfoxide cc- 100 Example 5.Ointment composition The following ingredients are combined into an ointment form which contains dimethyl sulfoxide at a concentration of 45%.

Gms. Carbowax 4000 675 Dimethyl sulfoxide (100%) 67 5 Isotonic saline 150 Example 6.--Lotion composition Acid mantle lotion base is a buffered aluminum acetate in a Water-miscible emulsion base supplied by the Dome Chemical Company of New York. A 25% dimethyl sulfoxide cream was made as follows: Acid mantle cream base -gms 75 Dimethyl sulfoxide (100%) cc 25 Example 7.-Cream composition Acid mantle cream base is also a buffered aluminum acetate in a water-miscible emulsion base supplied by Dome Chemical Company of New York. A dimethyl sulfoxide cream was made as follows:

Gms. Acid mantle cream base 80 Dimethyl sulfoxide (100%) 20 Example 8.Compositions for topical treatment Dilutions of DMSO with glycerin may be prepared by proportional mixing to obtain compositions with 10% to 40% glycerin. The glycerin serves as both a diluent and a thickening agent.

Example 9.Spray composition forms DOSAGES AND ROUTES OF ADMINISTRATION The following is a general description of the manner of use of the compositions and dosage forms of this invention. For an additional discussion thereof which may be of use to the practitioner, reference is made to applicants copending application Serial No. 686,295, filed Nov. 28, 1967.

Dimethyl sulfoxide can be effectively administered topically to the skin and mucous membranes of the various body cavities as by direct application or installation. Topical applications are of particular advantage where a local effect is desired. As discussed in detail under that heading, composition and dosage forms of dimethyl sulfoxide are provided which incorporate pharmaceutical diluents, ex cipients or adjuvants. For topical use, concentrations of from 10% to and above for application to mucous membranes and at least about 50% for dermal applications are indicated. The more advantageous concentrations and composition forms for particular routes of administration will also be discussed at a later point.

The dosage and frequency of administration will be determined by the expertise of the attending practitioner who considers the nature and severity of the disorder, the area involved, the response desired or observed and the subject. Generally, as illustrated by the disclosure of application Ser. No. 686,295, the dosage may be as low as 0.01 gram per kilogram body weight and the optimum amount anywhere from around 0.02 to 0.05 up to 1.0 gram per kilogram of body weight per day or somewhat higher in a few instances. The average individual dose may be in the neighborhood of 0.1 to 0.2 gram per kg. body weight. However, the optimum dose will depend to a considerable extent upon the type and extent of the disorder and the mode of application.

The treatment may be repeated once or twice daily, or even more frequently, until appropriate response is obtained or for the duration of the complaint. For some indications (such as many acute situations), only one or two applications involving a few cubic centimeters of dimethyl sulfoxide may be necessary while in chronic situations a more sustained regimen for a prolonged period or follow-up treatments may be called for. In any case, the optimum amount for a given disorder will depend upon the factors previously mentioned.

Wherever feasible, it may be desirable to administer the dimethyl sulfoxide locally to the involved area to achieve maximum concentrated effect. In such cases where a localized effect is desired, the dimethyl sulfoxide compositions may be applied directly to the area involved, as by wetting skin or mucous membrane.

The following example is illustrative:

Example 10 A 28-year-old female subject was seen with seborrheic dermatitis of the scalp. Thirty percent dimethyl sulfoxide in water with a lotion base was applied in four cc. volume three times daily for three days. At the end of one week, all local evidence of the dandruff was gone. The benefit in this chronic inflammation lasted for three weeks; the subject was treated at that time for recurrence, again with three days treatment with the same schedule as the first treatment. This time the benefit lasted for two months.

When a more generalized effect is desired, as in the case of widespread involvements, topical application to a surface area rich in blood vessels (as for example in the chest, back, legs and arms) is quite convenient. Higher concentrations are preferred for topical applications, such as at least 25 and more often, at least about 50%. Desirably, at each application the surface involved is thoroughly wetted. Where large areas are to be treated, it may be desirable to treat an entire limb, torso, or body with a dilute aqueous solution of dimethyl sulfoxide. At the lower concentrations greater volumes of dimethyl sulfoxide solutions may be administered more frequently. Less frequent applications may be effectively made with solultions containing at least about 50% of dimethyl sulf- 0X1 e.

The foregoing invention can now be practiced by those skilled in the art. Such skilled persons will know that the invention is not necessarily restricted to the particular embodiments presented herein. The scope of the invention is to be defined by the terms of the following claims, as given meaning by the preceding description.

We claim:

ll. A sterile pharmaceutical composition containing dimethyl sulfoxide as an essential, active pharmaceutical agent, suitable for topical application to achieve adequate tissue penetration of the dimethyl sulfoxide for a pharmaceutical effect, which comprises between about 10% and about by weight of highly purified, substantially pyrogen-free dimethyl sulfoxide, a tissue irritation-decreasing amount of a first non-active component consisting of a pharmaceutically acceptable, non-thickening hydrophilic diluent and a second non-active component consisting of a pharmaceutically acceptable water-dispersible thickening agent in an amount to materially increase the viscosity of the composition and thus to retard run-01f following topical application thereof.

2. The composition as in claim 1 and wherein said diluent comprises a hydrophilic diluent selected from water, glycerin and ethyl alcohol in an amount of at least about by weight of said composition.

3. A composition as in claim 2 and wherein said thickening agent is a synthetic polymer and said diluent is water.

4. A composition as in claim 2 and wherein said composition is in unit dosage form containing between about 0.5 gram and grams of dimethyl sulfoxide.

5. A composition as in claim 2 in the form of a lotion and containing a lotion base.

6. A composition as in claim 1 and wherein said composition is in multiple dosage form in a sterile container convenient for dosing, said container being filled with said composition and containing a volume of from about 20 cc. to about 500 cc. thereof.

7. A composition as in claim 1 and wherein DMSO is the sole active pharmacological agent in said composition.

8. A non-mobile, semisolid pharmaceutical composition containing dimethyl sulfoxide as an essential, active pharmaceutical agent, suitable for topical application to achieve adequate tissue penetration of the dimethyl sulfoxide for a pharmaceutical effect, which comprises between about 10% and about 90% by weight of highly purified, substantially pyrogen-free dimethyl sulfoxide, a tissue irritation-decreasing amount of a pharmaceutically acceptable hydrophilic diluent selected from water, glycerin and ethyl alcohol and a pharmaceutically acceptable water-dispersible thickening agent, capable of releasing the dimethyl sulfoxide at body temperature, in an amount sufiicient to render said composition semisolid.

9. A composition as in claim 8 in the form of a suppository.

10. A composition as in claim 8 wherein said diluent comprises water in an amount of at least about 10% by weight of said composition.

11. A composition as in claim 8 and wherein said composition contains at least about 50% by weight of dimethyl sulfoxide and said composition is in the form of an ointment.

12. A pharmaceutical composition containing dimethyl sulfoxide as an essential, active pharmaceutical agent, suitable for topical application to achieve adequate tissue penetration of the dimethyl sulfoxide for a pharamceutical effect, which comprises between about 10% and about 90% by weight of a highly purified, substantially pyrogen-free dimethyl sulfoxide and an emulsion base consisting of an emulsifying agent, a lipoid phase and an aqueous phase, said DMSO being incorporated in said aqueous phase, siad emulsion base present in an amount to materially increase the viscosity of the composition and thus to retard run-off following topical application thereof.

13. A composition as in claim 12 and wherein the DMSO concentration is at least about 50% by weight.

14. A composition as in claim 12 wherein said DMSO is the sole active pharmacological agent in said composition.

15. A sterile pharmaceutical composition containing dimethyl sulfoxide as an essential, active pharmaceutical agent, suitable for topical application to achieve adequate tissue penetration of the dimethyl sulfoxide for a pharmaceutical effect, which comprises between about 10% and about by weight of highly purified, substantially pyrogen-free dimethyl sulfoxide, a tissue irritation-decreasing amount of a pharmaceutically acceptable hydrophilic diluent and a pharmaceutically acceptable dimethyl sulfoxide-soluble lipoidal thickening agent in an amount to materially increase the viscosity of the composition and thus to retard run-off following topical application thereof.

16. A composition as in claim 15 and wherein said DMSO is the sole active pharmacological agent in said composition.

17. A suppository containing dimethyl sulfoxide as an essential, active pharmaceutical agent, suitable for topical application to body cavities to achieve adequate tissue penetration of the dimethyl sulfoxide for a pharmaceutical effect, which comprises a suppository base capable of releasing dimethyl sulfoxide when the suppository is administered and an effective amount of dimethyl sulfoxide to achieve a pharmaceutical effect.

18. A suppository as in claim 17 and wherein said dimethyl sulfoxide comprises between about 10% to 50% by weight of said suppository.

19. A container provided with liquid spray-dispensing means and containing a fluid, sprayable composition which comprises an amount of DMSO elfective to enhance external membrane penetration of said agent and comprising at least about 10% by weight of said composition and an aqeuous diluent comprising water in a concentration of at least about 10% by weight of said composition.

20. A container as in claim 19 and wherein said DMSO in the composition charged therein comprises at least about 50% by weight of said composition.

21. A container as in claim 19 and wherein said container is an aerosol bomb containing a halocarbon propellent.

22. A container as in claim 19 and wherein said container is a squeeze bottle.

23. A container as in claim 19 and wherein the composition therein contains at least about 50% by weight of water.

24. A container as in claim 23 and wherein said aqueous diluent contains a physiological salt in a concentration to render said composition isotonic.

References Cited UNITED STATES PATENTS 3,549,770 12/1970 Herschler 424337 3,551,554 12/1970 Herschler 4247 3,592,936 7/1971 Marcus et a1. 424-337 3,499,961 3/1970 Dobson et a1. 42468 3,011,950 12/1961 Mehaffey 424-81 FOREIGN PATENTS 655,363 10/1965 Republic of South Africa.

OTHER REFERENCES Marson: Bull. Chimicofarm 102: 109-124, February 1963.

Fitzpatrick: D & CI 96(2): 254, February 1965.

SHEP K. ROSE, Primary Examiner U.S. Cl. X.R. 4243.37

UNITED STATES. PATENT OFFICE vCERTIFICATE OF CORRECTION Patent No. 3,140,420 Dated June 19, 197-3 PRINTER'S TRIM LINE I ROBERT J. HERSCHLER, ET. AL.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

On the cover sheet insert The portion of the term of this patent subsequent to Dec. 22, 1987, has been disclaimed,

Signed and sealed this 21st day of January 1975.

(SEAL) Attest:

MCCOY M. GIBSON JR. C MARSHALL DANN Attesting Officer Commissioner of Patents FORM PO-1050 10-69) USCOMM-DC 60376-P69 u.s. covemquzm rmu'rme orrlc: 8 93 o 

